Resting state block and use independence of rat vascular muscle Ca++ channels by Ro 40-5967

Blocking actions of the novel Ca++ antagonist, Ro 40-5967 ((1S,2S)-2-[2[[3-(2-benzimidazolylpropyl] methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-++naphthyl+ ++ methoxyacetate dihydrochloride), on divalent inward currents were characterized in spontaneously active vascular muscle cells (VMC) of neonatal rat azygos veins. Ca++ channel currents (ICa) were reduced by Ro 40-5967 in a concentration range from 0.1 to 10 microM, effective within the first 5 min of exposure. ICa were decreased by up to 70% during the first stimulus test pulse and remained constant during subsequent pulses, and were not shifted along the voltage axis, as determined by peak current-voltage plots. There was no change in apparent threshold or the voltage (+20 mV) at which maximum inward current occurred. Block of Ba++ currents through VMC Ca++ channels occurred independent of membrane potential, even when holding potential was as negative as -80 mV. ICa were blocked to the same absolute values from holding potential = -30 mV. Thus, ICa block occurred equally during the first pulse and at all subsequent time points, i.e., under conditions in which VMC Ca++ channels were in the resting state, inactive state, or open state. To search further for use-dependent effects of Ro 40-5967, we stimulated at higher frequencies (up to 0.3/sec), but there was no change in fractional block with frequency or stimulus repetition and thus no use dependence of the block of VMC Ca++ channels by Ro 40-5967.(ABSTRACT TRUNCATED AT 250 WORDS)